Results of a planned interim overall survival analysis of the phase III monarchE trial offered further support for the addition of abemaciclib to adjuvant endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive, high-risk disease, according to Stephen R.D. Johnston, MD, PhD, of the Royal Marsden NHS Foundation Trust, London, who reported the study update at the 2022 San Antonio Breast Cancer Symposium.1
“In the monarchE trial, with additional follow-up, the benefit of adjuvant abemaciclib deepened in magnitude, with an increase in absolute invasive disease–free and distant recurrence–free survival benefit at 4 years, as compared with the 2-year and 3-year rates,” Dr. Johnston said.
At the 4-year timepoint, the difference in invasive disease–free survival favoring the cyclin-dependent kinase 4 and 6 (CDK4/6) abemaciclib was 6.4%, compared with a 4.8% difference observed at 3 years and a 2.8% difference at 2 years. The results were simultaneously published in The Lancet Oncology.2
The benefit of adjuvant abemaciclib deepened in magnitude, with an increase in absolute invasive disease–free and distant recurrence–free survival benefit at 4 years, as compared with the 2-year and 3-year rates.— Stephen R.D. Johnston, MD, PhD
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“Benefit was demonstrated across all prespecified subgroups. Ki67 remained prognostic, but the abemaciclib benefit was similar regardless of Ki67 index,” Dr. Johnston said.
Although the overall survival data remain immature at this time, fewer deaths were observed with abemaciclib plus endocrine therapy compared with endocrine therapy alone, he further reported.
Study Details
The randomized, open-label, phase III monarchE trial enrolled 5,637 patients with hormone receptor–positive, HER2-negative, node-positive, early-stage breast cancer deemed at high risk based on clinicopathologic features (cohort 1, 91% of patients) or Ki67 index of at least 20% (cohort 2, 9% of patients). Although the study could include untreated patients, Dr. Johnston said, 95% of patients on the trial received either neoadjuvant or adjuvant chemotherapy.
Patients received 2 years of treatment with endocrine therapy (aromatase inhibitor or tamoxifen) alone or with abemaciclib at 150 mg twice daily. The primary objective was invasive disease–free survival.
In the previously reported primary analysis, adjuvant abemaciclib plus endocrine therapy demonstrated a significant improvement in both invasive disease–free and distant recurrence–free survival.3 The current preplanned analysis was conducted 2 years later and represents a 4-year landmark analysis. Patients were followed for a median of 4 years and currently are all off abemaciclib.
Efficacy of Combination Therapy at 4 Years
After 4 years, the rate of invasive disease–free survival was 85.8% with abemaciclib plus endocrine therapy vs 79.4% with endocrine therapy alone (hazard ratio [HR] = 0.664; P < .0001). Invasive disease–free survival rates were previously reported to be 92.7% vs 89.9%, respectively, at 2 years3 and 89.2% vs 84.4% at 3 years.4
“For the updated efficacy results for the primary outcome of invasive disease–free survival in the intent-to-treat population, you can see that with further follow-up, the Kaplan-Meier curves continue to separate beyond completion of the 2 years of abemaciclib treatment, suggesting a potential carryover effect,” Dr. Johnston said. He noted that the benefit of abemaciclib was consistent across all prespecified subgroups.
Beyond the completion of treatment, a benefit in terms of distant relapse–free survival also persisted. At 4 years, these rates were 88.4% with abemaciclib plus endocrine therapy vs 82.5% with endocrine therapy alone (HR = 0.659; P < .0001). This 5.9% difference—representing a 34.1% reduction in risk—was an increase over the rates of 2.5% at 2 years3 and 4.1% at 3 years,4 he noted.
“Overall survival data remain immature, but we can see a numerical difference, with 157 deaths with abemaciclib vs 173 with endocrine therapy alone,” he said. Twice as many patients have developed metastatic disease: 249 treated with endocrine therapy alone and 125 treated with abemaciclib plus endocrine therapy.
Efficacy Outcomes by Cohort
Hazard ratios were determined for the two cohorts. For cohort 1 (at high risk by clinicopathologic features) and for cohort 2 (high risk by Ki67 index), the hazard ratios were 0.653 and 0.773, respectively, for invasive disease–free survival. For distant relapse–free survival, the hazard ratios were 0.652 for cohort 1 and 0.764 for cohort 2.
KEY POINTS
- In a planned interim overall survival analysis of the phase III monarchE trial, abemaciclib plus endocrine therapy was evaluated as adjuvant treatment of patients with hormone receptor–positive, HER2-negative, node-positive, high-risk breast cancer vs endocrine therapy alone.
- At the 4-year mark, there was an absolute 6.4% difference in invasive disease–free survival favoring abemaciclib.
- Benefit was observed across all levels of Ki67 expression.
- The magnitude of benefit of this treatment approach appears to be increasing over time.
In cohort 1, pretreatment biopsies analyzed for Ki67 found it to be prognostic of outcomes but not predictive of abemaciclib benefit. “Similar abemaciclib treatment effects were observed regardless of Ki67 index,” he said. He noted that 2,003 patients had high Ki67 index levels, whereas 1,914 had low Ki67 levels, and the relative risk reduction with abemaciclib was 38% in each group.
The 4-year invasive disease–free survival rates were 83.6% with abemaciclib plus endocrine therapy and 74.7% with endocrine therapy alone (HR = 0.618) in the Ki67-high group. In the Ki67-low group, these rates were 88.8% and 82.4%, respectively (HR = 0.624).
The safety data were consistent with previous analyses, with no new safety signals emerging. Diarrhea was a predominant symptom, reported by 84% of patients (all grades); in general, 44% of patients had doses reduced because of adverse events.
Responding to a question regarding the optimal dosing vis a vis toxicity, Dr. Johnston said: “I’m very clear with my patients that we find the dose that is right for them, one they can tolerate and is likely to produce a therapeutic benefit.”
DISCLOSURE: Dr. Johnston has received honoraria from or served as a consultant or advisor to Pfizer Novartis, Eisai, AstraZeneca, Roche, Eli Lilly, and Puma Biotechnology.
REFERENCES
1. Johnston SRD, Toi M, O’Shaughnessy J, et al: Abemaciclib plus endocrine therapy for HR+, HER2– node-positive, high-risk dearly breast cancer: Results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes. 2022 San Antonio Breast Cancer Symposium. Abstract GS1-09. Presented December 6, 2022.
